Cytotoxicity and enhancement of the insulin signaling pathway induced by peroxidovanadium(V) complexes

•The pVs transmitted the insulin-mimetic signaling while it induced the generation of ROS.•The cytotoxicity of pVs was improved by elimination of ROS, but insulin-mimetic signaling of pVs also weakened.•Activation of stress signaling by ROS is one of the causes of cell death.

Vanadium compounds are known to possess a variety of physiological actions, including insulin-mimetic activities. We synthesized two peroxidovanadium(V) complexes (pVs) having the amino acid derivative N-(4-imidazolylmethyl)-l-alanate (imala) or N-(4-imidazolylmethyl)-l-phenylalanate (imphe) as an ancillary ligand. The pVs stimulated the proliferation of H4IIEC3 rat hepatoma cells at low doses while they resulted in cytotoxicity at high concentrations. Their insulin-mimetic activities were comparable to vanadium complexes. The signal transduction pathways induced by these compounds were examined in an effort to understand their suitability for therapeutic applications. When the cells were treated with the pVs, reactive oxygen species (ROS) were generated, and increased in a dose-dependent manner. In addition, the activation of cellular stress signals was also enhanced in a dose-dependent manner. It was found that ROS generated by the treatment with pVs at a high dose act as a stress inducer for the cells.

Graphical abstractWe synthesized two peroxidovanadium(V) complexes (pVs) which showed insulin-mimetic activities. We examined the signal transduction pathways induced by these compounds and found the reactive oxygen species (ROS) generation from these compounds. The ROS generated by these compounds induced the signal transduction pathway which resulted in the cell survival/death pathway.Figure optionsDownload full-size imageDownload as PowerPoint slide